Eukaryotic DNA is highly organized and packaged in the nucleus. The organization and packaging are achieved through the addition of proteins, including core histones H2A, H2B, H3 and H4, which form a complex structure, the chromatin, together with DNA. The modification of core histones is of fundamental importance to conformational changes of the chromatin. The level of acetylation is related to transcription activity, and then the acetylation induces an open chromatin conformation that allows the transcription machinery access to promoters. Histone deacetylase (HDAC) and histone acetyltransferase (HAT) are enzymes that influence transcription by selectively deacetylating or acetylating the ε-amino groups of lysine located near the amino termini of core histone proteins. HDACs are a family of 18 enzymes (isoforms) that may act as master regulators of many diseases, including cancer, because they are involved in the control of gene expressions. Disruption of HDACs has been linked to a wide variety of human cancers. HDAC enzymes or isoforms appear to be involved in many different types of cancer.
Histone deacetylase (HDAC) inhibitors are emerging as an exciting new class of potential anticancer agents for the treatment of solid and hematological malignancies. In recent years, an increasing number of structurally diverse HDAC inhibitors have been identified; they inhibit proliferation and induce differentiation and/or apoptosis of tumor cells in cultures and in animal models. HDAC inhibition causes acetylated nuclear histones to accumulate in both tumoral and normal tissues, providing a surrogate marker for the biological activity of HDAC inhibitors in vivo. The effects of HDAC inhibitors on gene expression are highly selective, leading to transcriptional activation of certain genes such as the cyclin-dependent kinase inhibitor p21WAF1/CIP1 but repression of others. HDAC inhibition results in acetylation of not only histones but also transcription factors such as p53, GATA-1 and estrogen receptor-alpha. The functional significance of acetylation of non-histone proteins and the precise mechanisms whereby HDAC inhibitors induce tumor cell growth arrest, differentiation and/or apoptosis are currently the focus of intensive research. HDAC inhibitors currently in clinical trials have shown activity and represent a class of molecularly targeted anti-tumor agents with potential for efficacy based on a novel mechanism of action.
A review article published in Medicinal Research Reviews, Vol. 26, No. 4, pp. 397-413, 2006 states that four classes of HDAC inhibitors, short-chain fatty acids, hydroxamic acids, benzamides and cyclic peptides, had been reported. Hydroxamic acid-based hybrid polar compounds (HPCs) are HDAC inhibitors, which induce differentiation at micromolar or lower concentrations (Journal of the National Cancer Institute, Vol. 92, No. 15, Aug. 2, 2000, pp. 1210-1216). U.S. Pat. No. 6,174,905, EP 0847992, JP 258863/96, and Japanese Application No. 10138957 disclose that benzamide derivatives induce cell differentiation and inhibit HDAC. SNDX-275 (Entinostat) especially disclosed in Example 48 of U.S. Pat. No. 6,174,905 has become a candidate for cancer treatment drug. WO 01/38322 discloses additional compounds that serve as HDAC inhibitors. It is reported in Hum Genet, 2006, 120, pp. 101-110 that the benzamide M344 up-regulates SMN2 protein expression in fibroblast cells derived from SMA patients up to 7-fold after 64 hours of treatment. It is reported that sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy (Human Molecular Genetics, 2004, Vol. 13, No. 11, pp. 1183-1192). Trichostatin A, a histone deacetylase inhibitor, was found to induce ubiquitin-dependent cyclin D1 degradation in MCF-7 breast cancer cells (Molecular Cancer 2006, 5:8). U.S. Pat. No. 7,169,801 discloses that compounds having the formula of Z-Q-L-M or Z-L-M may be used to inhibit histone deacetylase. U.S. Pat. No. 6,888,027 covers a family of Sulphonamide HDAC inhibitors including PXD101. European Patent Number EP 1 301 184 covers the use of valproic acid and derivatives as HDAC inhibitors in the treatment of solid tumors. WO0222577 indicates that hydroxamate compounds are inhibitors of histone deacetylase and are useful aspharmaceuticals for the treatment of proliferative diseases. Moreover, the anti-diabetic activity of HDAC inhibitors is reported in the FASEB Journal, 2008, Vol. 22, pp. 944-945 and Diabetes, 2008, Vol. 57, pp. 860-867.
N,N′-hexamethylene bisacetamide (HMBA) is an effective inducer of differentiation in a number of transformed cell lines. U.S. Pat. Nos. 6,087,367 and RE38506 reports that a number of compounds related to HMBA with polar groups separated by apolar linkages on a molar basis, are as active or 100 times more active than HMBA. Furthermore, U.S. Pat. No. 7,399,787 reports that histone deacetylase inhibitors related to HMBA such as suberoylanilide hydroxamide acid (SAHA) have the ability to induce growth arrest, differentiation and/or apoptosis of tumor cells. In addition, Laurence Catley et al. reports that NVP-LAQ824 (a hydroxamic acid derivative) and NVP-LAQ824 (a derivative of 4-aminomethylcinnamic hydroxamic acid) are potent histone deacetylase inhibitors (Blood, 1 October 2003, Vol. 102, No. 7, pp. 2615-2622). George P et al. reports that LBH589 induces growth inhibition and regression in tumor cell lines by triggering apoptosis and LBH589 is now being tested in phase I clinical trials as an anticancer agent (Blood 105(4): 1768-76 Feb. 15, 2005). Other histone deacetylase inhibitors known in the art include pyroxamide, M-carboxycinnamic acid bishydroxamide (CBHA), trichostatin A (TSA), trichostatin C, salicylihydroxamic acid (SBHA), azelaic bishydroxamic acid (ABHA), azelaic-1-hydroxamate-9-anilide (AAHA), 6-(3-chlorophenylureido) carpoic hydroxamic acid (3C1-UCHA), oxamflatin, A-161906, scriptaid, PXD-101, cyclic hydroxamic acid-containing peptide (CHAP), ITF-2357, MW2796, MW2996, trapoxin A, FR901228 (FK 228 or Depsipeptide), FR225497, apicidin, CHAP, HC-toxin, WF27082, chlamydocin, sodium butyrate, isovalerate, valerate, 4-phenylbutyrate (4-PBA), 4-phenylbutyrate sodium (PBS), arginine butyrate, propionate, butyramide, isobutyramide, phenylacetate, 3-bromopropionate, tributyrin, valproic acid, valproate, CI-994, 3′-amino derivative of MS-27-275, MGCD0103 and Depudecin (U.S. Publication No. 20080242648).
However, there is still a need to develop a new class of HDAC inhibitors to prevent or treat cancers and other diseases involving HDAC.